The present invention relates to new anticholinergics of general formula 1
wherein A, X−, and the groups R1, R2, R3, R4, R5, R6, R7, and R8 have the meanings given herein, processes for preparing them, and their use as pharmaceutical compositions.
Anticholinergics may be used therapeutically in a variety of complaints. Particular mention should be made here, for example, of the treatment of asthma or chronic obstructive pulmonary disease (COPD). For treating these diseases WO 92/16528 proposes anticholinergics which have a scopine, tropenol, or tropine basic structure. The objective on which WO 92/16528 is based is to prepare compounds with an anticholinergic activity which are characterized by a long-lasting activity. To solve this problem, WO 92/16528 discloses, inter alia, benzilic acid esters of scopine, tropenol, or tropine.
For treating chronic diseases it is often desirable to prepare pharmaceutical compositions having a fairly long duration of activity. As a rule, this ensures that the concentration of the active substance needed in the body to achieve the therapeutic effect is provided over a fairly long period of time without having to administer the drug too frequently. Moreover, administering an active substance at fairly long time intervals makes a major contribution to the patient's well being. It is particularly desirable to provide a drug which can be used in a therapeutically beneficial manner by a single application per day (single dose). The use of a drug once a day has the advantage that the patient can become accustomed relatively quickly to regularly taking the drug at certain times of the day.
In order to be used as a medicament for use once a day, the active substance to be given must meet particular requirements. First of all, the onset of the desired activity should take place relatively quickly after administration of the drug and ideally should have as constant an effect as possible over a subsequent fairly long period of time. On the other hand, the duration of activity of the drug should not substantially exceed a period of about one day. Ideally, an active substance has an activity profile such that the preparation of a drug for administration once a day, which contains the active substance in therapeutically beneficial doses, can be deliberately controlled.
It has been found that the benzilic acid esters of scopine, tropenol, and tropine disclosed in WO 92/16528 do not meet these stringent requirements. Because of their extremely long period of activity, which significantly exceeds the above-mentioned period of about one day, they cannot be used therapeutically for administration in a single dose per day.
The aim of the present invention is therefore to provide new anticholinergics which, by virtue of their activity profile, make it possible to prepare a drug for administration once a day. A further objective of the invention is to prepare compounds characterized by a relative rapid onset of activity. The invention further sets out to provide compounds which, after a rapid onset of activity, have as constant an activity as possible over a subsequent lengthy period of time. A further aim of the invention is to provide compounds whose duration of activity does not substantially exceed a period of about one day in therapeutically beneficial doses. Finally, the invention sets out to provide compounds which have an activity profile which ensures good control of the therapeutic effect (i.e., total therapeutic effect without side effects caused by a build-up of the substance in the body).